WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200771
Description: CI-1040, also known as PD184352, is a MEK inhibitor, which demonstrated in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated.
MedKoo Cat#: 200771
Chemical Formula: C17H14ClF2IN2O2
Exact Mass: 477.97565
Molecular Weight: 478.66
Elemental Analysis: C, 42.66; H, 2.95; Cl, 7.41; F, 7.94; I, 26.51; N, 5.85; O, 6.69
Synonym: CI1040; CI-1040; CI 1040; PD184352; PD 184352; PD-184352.
IUPAC/Chemical Name: 2-(2-Chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide
InChi Key: GFMMXOIFOQCCGU-UHFFFAOYSA-N
InChi Code: InChI=1S/C17H14ClF2IN2O2/c18-12-7-10(21)3-6-14(12)22-16-11(4-5-13(19)15(16)20)17(24)23-25-8-9-1-2-9/h3-7,9,22H,1-2,8H2,(H,23,24)
SMILES Code: O=C(NOCC1CC1)C2=CC=C(F)C(F)=C2NC3=CC=C(I)C=C3Cl
CI-1040 (PD184352) is an orally active, highly specific, small-molecule inhibitor of one of the key components of this pathway (MEK1/MEK2), and thereby effectively blocks the phosphorylation of ERK and continued signal transduction through this pathway. Antitumor activity has been seen in preclinical models with this compound, particularly for pancreas, colon, and breast cancers, which has been shown to correlate with its inhibition of pERK. Clinically, CI-1040 has been shown to be well tolerated in phase I studies, with safety and pharmacokinetic profiles that permit continuous daily dosing. Biomarker studies have shown target inhibition in patients, and antitumor activity has also been observed with a partial response in one patient with pancreatic cancer and stable disease in approximately 25% of phase I patients. Given the central role of the ERK/mitogen-activated protein kinase pathway in mediating growth-promoting signals for a diverse group of upstream stimuli, inhibitors of MEK, as a key central mediator, could have significant clinical benefit in the treatment of breast and other cancers.
However, in Phase II trials, CI-1040 demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.
1: Ou DL, Shen YC, Liang JD, Liou JY, Yu SL, Fan HH, Wang DS, Lu YS, Hsu C, Cheng AL. Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma. Clin Cancer Res. 2009 Sep 15;15(18):5820-8. Epub 2009 Sep 8. PubMed PMID: 19737956.
2: Henderson YC, Ahn SH, Clayman GL. Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040. Arch Otolaryngol Head Neck Surg. 2009 Apr;135(4):347-54. PubMed PMID: 19380355.
3: Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM, Delaney AM, Kaufman M, LePage S, Leopold WR, Przybranowski SA, Sebolt-Leopold J, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA Jr, Smith Y, Warmus JS, Tecle H. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6501-4. Epub 2008 Oct 15. PubMed PMID: 18952427.
4: Liu D, Liu Z, Jiang D, Dackiw AP, Xing M. Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations. J Clin Endocrinol Metab. 2007 Dec;92(12):4686-95. Epub 2007 Oct 2. PubMed PMID: 17911174.
5: Martin L. PD184352 releases the regular hypoxic reversible DNA replication arrest in T24 cells. J Biochem Mol Biol. 2007 Nov 30;40(6):895-8. PubMed PMID: 18047784.
6: Hidalgo M, Amador ML, Jimeno A, Mezzadra H, Patel P, Chan A, Nielsen ME, Maitra A, Altiok S. Assessment of gefitinib- and CI-1040-mediated changes in epidermal growth factor receptor signaling in HuCCT-1 human cholangiocarcinoma by serial fine needle aspiration. Mol Cancer Ther. 2006 Jul;5(7):1895-903. PubMed PMID: 16891476.
7: Mattingly RR, Kraniak JM, Dilworth JT, Mathieu P, Bealmear B, Nowak JE, Benjamins JA, Tainsky MA, Reiners JJ Jr. The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines. J Pharmacol Exp Ther. 2006 Jan;316(1):456-65. Epub 2005 Oct 20. PubMed PMID: 16239399.
8: Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, DeLuca P, Bruzek L, Piens J, Asbury P, Van Becelaere K, Herrera R, Sebolt-Leopold J, Meyer MB. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005 Aug 10;23(23):5281-93. Epub 2005 Jul 11. PubMed PMID: 16009947.
9: Wang Y, Van Becelaere K, Jiang P, Przybranowski S, Omer C, Sebolt-Leopold J. A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040. Neoplasia. 2005 Apr;7(4):336-47. PubMed PMID: 15967111; PubMed Central PMCID: PMC1501146.
10: McDaid HM, Lopez-Barcons L, Grossman A, Lia M, Keller S, PÃ©rez-Soler R, Horwitz SB. Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. Cancer Res. 2005 Apr 1;65(7):2854-60. PubMed PMID: 15805287.